QSAR AND MOLECULAR MODELING OF CATAMPHIPHILIC DRUGS ABLE TO MODULATE MULTIDRUG-RESISTANCE IN TUMORS

The Free-Wilson approach was applied to two groups of catamphiphilic m ultidrug resistance (MDR) modifiers using classical multiple linear re gression (MLR) and genetic algorithms (GA) for feature selection. In t he first group (17 thioxanthenes) the side chain length between the ri ng system and tertiary nitrogen, the type of the tertiary nitrogen sub stituent and the stereoisomery were found to be significant for anti-M DR activity both by MLR and GA (r(2) = 0.803, predictive power Q(2) = 0.652). In the second data set (17 phenothiazines and related drugs) t he ring system type, the stereoisomery, the side chain type, and the r ing substituent kind in position two contributed significantly (r(2) = 0.938 and Q(2) = 0.908). The QSAR studies showed a thioxanthene ring with a -CF3 substituent in position two, a piperazine moiety with a 4- bond distance from the ring system and trans-isomery to be optimal for MDR reversal. Based on these results molecular modeling of trans-(T) and cis-flupentixol (C) was performed assuming that the 2 to 3-fold di fference in MDR reversing activity of T compared to C might be related to different preferable conformations in the membrane lipid environme nt. Among all conformations generated by the SYBYL systematic search r outine those comprising local energy minima were selected and optimize d with semiempirical quantum chemistry methods. The optimized conforma tions were compared with H-1-NMR analysis results on drug conformation s in lipid environment, some of them corresponded excellently. The ele ctrostatic and lipophilic fields of T and C were compared to identify molecular properties related to the activity difference. The results d emonstrated that T and C could have a different (mirrorlike) orientati on entering the lipid bilayer by the ring system suggesting much bette r fitting of T compared to C to the lipid ''MDR-reversal receptor''.